Crystalline forms of donepezil hydrochloride

ABSTRACT

The present invention provides novel crystalline forms of donepezil hydrochloride, processes for their preparation and pharmaceutical compositions containing them.

FIELD OF THE INVENTION

The present invention provides novel crystalline forms of donepezilhydrochloride, processes for their preparation and pharmaceuticalcompositions containing them.

BACKGROUND OF THE INVENTION

Donepezil hydrochloride of formula (1):

or2,3-Dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-onehydrochloride is useful for prevention and treatment of alzheimerdisease. The therapeutic uses of donepezil hydrochloride and relatedcompounds are disclosed in EP 296560.

U.S. Pat. No. 6,140,321 disclosed four crystalline forms of donepezilhydrochloride, polymorph (I), polymorph (II), polymorph (III) andpolymorph (IV) and processes for preparation thereof.

It has now been discovered that donepezil hydrochloride can be preparedin four stable crystalline forms having good dissolutioncharacteristics.

The object of the present invention is to provide stable novelcrystalline forms of donepezil hydrochloride, processes for preparingthese forms and pharmaceutical compositions containing them.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a novelcrystalline form of donepezil hydrochloride, designated as form H1,characterized by an x-ray powder diffraction spectrum having peaksexpressed as 2θ at about 15.2, 18.7, 20.6, 22.3, 23.5, 24.0, 24.6, 27.0,29.0 and 30.5 degrees. FIG. 1 shows typical form H1 x-ray powderdiffraction spectrum.

In accordance with the present invention, a process is provided forpreparation of donepezil hydrochloride form H1, which comprises:

-   a) dissolving donepezil free base in ethylene dichloride;-   b) adding hydrochloric acid; and-   c) precipitating donepezil hydrochloride form H1 from the solution    formed in (b) by adding an anti-solvent.

Preferably, the quantity of hydrochloric acid is 0.5 to 2.0 mole permole of donepezil. The anti-solvent should be added in the quantity thatcauses the precipitation of donepezil hydrochloride under the conditionsof experiment. Preferable anti-solvents are diisopropyl ether, n-hexane,n-heptane and diethyl ether. A mixture of anti-solvents may also beused.

In accordance with the present invention, an another process is providedfor preparation of donepezil hydrochloride form H1, which comprises:

-   a) dissolving donepezil free base in ethylene dichloride;-   b) precipitating donepezil hydrochloride form H1 from the solution    formed in (a) by adding an anti-solvent.

Donepezil hydrochloride in any form, crystalline, amorphous or solvatedform, may be used in (a). The anti-solvent should be added in a quantitythat causes the precipitation of donepezil hydrochloride under theconditions of experiment. Preferable anti-solvents are diisopropylether, n-hexane, n-heptane and diethyl ether. A mixture of anti-solventsmay also be used.

In accordance with the present invention, there is provided a novelcrystalline form of donepezil hydrochloride, designated as form H2,characterized by an x-ray powder diffraction spectrum having peaksexpressed as 2θ at about 6.6, 6.8, 10.1, 12.8, 13.7, 15.0, 15.6, 16.5,17.3, 18.4, 19.5, 19.8, 20.0, 21.6, 21.9, 22.3, 23.9, 24.2, 24.7, 25.3,26.0, 26.9 and 28.2 degrees. FIG. 2 shows typical form H2 x-ray powderdiffraction spectrum.

In accordance with the present invention, a process is provided forpreparation of donepezil hydrochloride form H2, which comprises:

-   a) dissolving donepezil free base in toluene;-   b) adding hydrochloric acid; and-   c) isolating donepezil hydrochloride form H2 by filtration or    centrifugation.

Preferably, the quantity of hydrochloric acid is 0.5 to 2.0 mole permole of donepezil.

In accordance with the present invention, there is provided a novelcrystalline form of donepezil hydrochloride monohydrate, characterizedby an x-ray powder diffraction spectrum having peaks expressed as 2θ atabout 5.0, 10.0, 12.7, 13.2, 16.2, 20.0, 21.3, 23.1, 23.9 and 25.3degrees. FIG. 3 shows donepezil hydrochloride monohydrate x-ray powderdiffraction spectrum.

In accordance with the present invention, a process is provided forpreparation of donepezil hydrochloride monohydrate, which comprises:

-   a) dissolving donepezil free base in a mixture of chloroform and    water;-   b) adding hydrochloric acid; and-   c) precipitating donepezil hydrochloride monohydrate from the    solution formed in (b) by adding an anti-solvent.

The water can be added directly or in the form of, for example, as anaqueous solution of hydrochloric acid. Preferably, the quantity ofhydrochloric acid is 0.5 to 2.0 mole per mole of donepezil. Preferableanti-solvents are diisopropyl ether, n-hexane, n-heptane and diethylether. A mixture of anti-solvents may also be used.

In accordance with the present invention, an another process is providedfor preparation of donepezil hydrochloride monohydrate, which comprises:

-   a) dissolving donepezil hydrochloride in a mixture of chloroform and    water; and-   b) precipitating donepezil hydrochloride monohydrate from the    solution formed in (a) by adding an anti-solvent.

Donepezil hydrochloride in any form, crystalline, amorphous or solvatedform, may be used in (a). The anti-solvent should be added in a quantitythat causes the precipitation of donepezil hydrochloride under theconditions of experiment. Preferable anti-solvents are diisopropylether, n-hexane, n-heptane and diethyl ether. A mixture of anti-solventsmay also be used.

In accordance with the present invention, there is provided a novelcrystalline form of donepezil hydrochloride sesquihydrate, characterizedby an x-ray powder diffraction spectrum having peaks expressed as 2θ atabout 5.1, 10.8, 12.8, 13.3, 13.9, 15.0, 16.3, 17.1, 17.7, 19.5, 20.1,21.4, 23.2, 24.1, 26.6, 27.3, 28.2, 29.7, 31.9 and 35.3 degrees. FIG. 4shows donepezil hydrochloride sesquihydrate x-ray powder diffractionspectrum.

In accordance with the present invention, a process is provided forpreparation of donepezil hydrochloride sesquihydrate, which comprises:

-   a) dissolving donepezil free base in a mixture of tert-butyl alcohol    and water;-   b) adding hydrochloric acid; and-   c) isolating donepezil hydrochloride sesquihydrate by filtration or    centrifugation.

The water can be added directly or in the form of, for example, as anaqueous solution of hydrochloric acid. Preferably, the quantity ofhydrochloric acid is 0.5 to 2.0 mole per mole of donepezil.

Donepezil free base and donepezil hydrochloride used in the aboveprocesses can be obtained from the previously known methods.

In accordance with the present invention, there is provided apharmaceutical composition comprising donepezil hydrochloride form H1and pharmaceutically acceptable carrier or diluent.

In accordance with the present invention, there is provided apharmaceutical composition comprising donepezil hydrochloride form H2and pharmaceutically acceptable carrier or diluent.

In accordance with the present invention, there is provided apharmaceutical composition comprising donepezil hydrochloridemonohydrate and pharmaceutically acceptable carrier or diluent.

In accordance with the present invention, there is provided apharmaceutical composition comprising donepezil hydrochloridesesquihydrate and pharmaceutically acceptable carrier or diluent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a x-ray powder diffraction spectrum of Donepezil hydrochlorideform H1.

FIG. 2 is a x-ray powder diffraction spectrum of Donepezil hydrochlorideform H2.

FIG. 3 is a x-ray powder diffraction spectrum of donepezil hydrochloridemonohydrate.

FIG. 4 is a x-ray powder diffraction spectrum of donepezil hydrochloridesesquihydrate.

x-Ray powder diffraction spectrum was measured on a Bruker axs D8advance x-ray powder diffractometer having a copper-Kα radiation.

The following examples further illustrate the present invention.

EXAMPLE 1

Donepezil free base (4.0 gm) is dissolved in ethylene dichloride (20 ml)at 27° C., conc. hydrochloric acid (1.2 ml) is added to the solution andstirred for 2 hours at 25° C. to 30° C. Then diisopropyl ether (75 ml)is added and the precipitated solid is filtered off and dried to give3.0 gm of donepezil hydrochloride form H1.

EXAMPLE 2

Donepezil free base (10.0 gm) is dissolved in toluene (50 ml) at 25° C.,conc. hydrochloric acid (2.8 ml) is added to the solution and stirredfor 6 hours at 25° C. to 30° C. The crystals formed are filtered anddried to give 8.2 gm of donepezil hydrochloride form H2.

EXAMPLE 3

Donepezil hydrochloride form H2 (5.0 gm) is added to ethylene dichloride(100 ml), the contents are heated to 55° C. and stirred for 8 hours at55° C. to 60° C. The solution so obtained is cooled to 25° C.,diisopropyl ether (100 ml) is added to the solution and precipitatedsolid is filtered and dried to give 4.3 gm of donepezil hydrochlorideform H1.

EXAMPLE 4

Donepezil free base (4.0 gm) is dissolved in a mixture of chloroform (20ml) and water (1 ml) at 25° C., conc. hydrochloric acid (1.4 ml) isadded to the solution and stirred for 3 hours at 25° C. to 30° C. Thendiisopropyl ether (100 ml) is added and precipitated solid is filteredoff and dried to give 4.0 gm of donepezil hydrochloride monohydrate.

EXAMPLE 5

Donepezil hydrochloride form H2 (5.0 gm) is added to a mixture ofchloroform (100 ml) and water (1.5 ml), the contents are heated to 45°C. and stirred for 8 hours at 45° C. to 50° C. The solution so obtainedis cooled to 25° C., diisopropyl ether (100 ml) is added to the solutionand precipitated solid is filtered and dried to give 4.1 gm of donepezilhydrochloride monohydrate.

EXAMPLE 6

Donepezil free base (4.0 gm) is dissolved in a mixture of tert-butylalcohol (30 ml) and water (1.5 ml) at 27° C., conc. hydrochloric acid(1.2 ml) is added to the solution and stirred for 3 hours at 25° C. to30° C. The crystals so obtained are filtered and dried to give 3.5 gm ofdonepezil hydrochloride sesquihydrate.

1. A process for the preparation of donepezil hydrochloride monohydratecharacterized by an x-ray powder diffraction spectrum having peaksexpressed as 2θ at about 5.0, 10.0, 12.7, 13.2, 16.2, 20.0, 21.3, 23.1,23.9 and 25.3 degrees, which comprises the steps of: a) dissolvingdonepezil free base in a mixture of chloroform and water; b) addinghydrochloric acid; and c) precipitating donepezil hydrochloridemonohydrate from the solution formed in (b) by adding an anti-solvent.2. The process according to claim 1, wherein the anti-solvent isdiisopropyl ether, n-hexane, n-heptane or diethyl ether.
 3. The processaccording to claim 1, wherein the anti-solvent is diisopropyl ether. 4.A process for preparation of donepezil hydrochloride monohydratecharacterized by an x-ray powder diffraction spectrum having peaksexpressed as 2θ at about 5.0, 10.0, 12.7, 13.2, 16.2, 20.0, 21.3, 23.1,23.9 and 25.3 degrees, which comprises the steps of: a) dissolvingdonepezil hydrochloride in a mixture of chloroform and water; and b)precipitating donepezil hydrochloride monohydrate from the solutionformed in (a) by adding an anti-solvent.
 5. The process according toclaim 4, wherein the anti-solvent is diisopropyl ether, n-hexane,n-heptane or diethyl ether.
 6. The process according to claim 4, whereinthe anti-solvent is diisopropyl ether.